New hydrophenanthrene compounds and process for their manufacture



compounds of the formula United States Patent r A Egg Patented Ap 1960 2,934,543 NEW HYDROPll-IENANTHRENE COMPOUNDS AND PROCESS FOR THEIR MANUFACTURE Tadeus Reichstein, Albert Wettstein, Georg Anner, Jean- Ren Billeter, and Karl Heusler, Basel, Robert Neher, Binningen, Julius Schmidlin, Basel, Hellmut Ueberwasser, Rieheu, and Peter Wieland, Basel, Switzerland; said Wettstein, Anner, Billeter, Hensler, Neher, Schmidlin, Ueberwasser, and Wieland, assignors to said Reichstein No Drawing. Application May 16, 1956 Serial No. 585,167 Claims priority, application Switzerland January 15, 1954 23 Claims. (Cl. 260-3403) Since this important hormone has so far been available only by a tedious extractive procedure from suprarenal glands of animals and could only be obtained in very low yield (40 to 95 mg. from 1000 kilos of fresh beef adrenals), asynthesis of this hormone and closely related 18-oxygenated hormones (e.g. the 18- hydroxy compound corresponding to aldosterone, viz. A -3z20-dioxo-llfl:18:21-trihydroxypregnene, that is 18- O-GH hydroxy-corticosterone which shows a similar high physiological activity) from readily available compounds either from other naturally occurring steroids or a total synthesis is of extraordinary technical importance.

The present invention thus provides a series of intermediates which can readily be converted into aldosterone or into the 18-hydroxy-corticosterone, thus making these hormones available in sufiicient quantity.

The present application more specifically relates to wherein X'stands for a ketalized oxo group, R for a hydrogen atom or a methyl group and R for a lower alkyl group is treated with a reducing agent capable of reducing a keto group to a carbinol group, such as an alkalimetal borohy'dride, followed by alkaline hydrolysis of the ester'grouping, lactonization of the carboxyl group in the 2-position with the hydroxyl group in the 4-position and oxidation of the hydroxyl group in the 1-position to an oxo group.

For the reduction of the oxo group in the l-position to a hydroxyl group according to the process of the invention. there are suitable primarily complex light metal hydrides, in particular sodium borohydride or lithium borohydride. suitable solvent, preferably an alcohol.

After the reduction of the oxo-group in the 1-position, the esterified groups in the 2- and 4-p0sition are hydrolized under alkaline condition, for example with an alkali metal hydroxide in a partly aqueous solution e.g. in an aqueous-alcoholic solution. In order to shorten 40 the reaction time it is of advantage to heat the reaction mixture to a temperature of about 50-100 C. The reduction of the oxo group and the hydrolysis of the ester functions can be eifected in the same reaction vessel without isolation of the intermediate product by simply adding water and the alkalimetal hydroxide, e.g. potassium hydroxide to the reducing mixture.

Upon acidification of the solution, the resulting hydroxy-acid partly lactonizes spontaneously. Lactonization is completed by heating the acid in an inert solvent, such as benzene. v i V The dehydrogenation of the hydroxyl group in the l-positiou to an oxo group can be eifected by various methods, particularly by using derivatives of hexavalent chromium. It has been observed that very satisfactory results are obtained with the chromium trioxide-pyridine complex, especially at a slightly elevated temperature. The compounds obtained in the above described reaction sequence are important intermediates in a process for the production of aldosterone. This process, which is described in detail in our copending applications Serial No. 585,142, filed May 16, 1956, now abandoned, and Serial No. 585,168, filed May 16, 1956, now abandoned, and Serial No. 585,144, filed May 16, 1956, now abandoned, and Serial No. 585,143, filed May 16, 1956, is

illustrated in the following diagram of formulae:

The reaction is carried out in a verted into aldos terone.

The starting materials for the process claimed are prepared from known hydrophenanthrene compound, especially from '4bp-methyl-7-ethylenedioxy-1:2:3:4:4au:4b:

:6:7:8: lGap-dodecahydrophenanthrene 1 one-4/8-ol by condensation with a dialkyl carbonate such as dimethyl ,or .diethylcarbonate in the presence of an alkaline condensing agent, e.g. sodium hydride,sodamide or sodium ethoxide. During this condensation not only a 2-carbalkoxy group is introduced but the 4,B-hydroxy group is simelts. at 99-101 C., and the labile form at 94 'C. with transformation.

. hon dioxide is introduced until a spot test on thymol niultaneously esterified to yield an alkoxy-carbonyloxy group. The ,B ketoester thus obtained is alkylated in the 2-position with an allylor methallyl halide, especially with an iodide to give a mixture of stereoisometric products which'may or may not be separated before reduction with an alkali metal borohydride according to the invention: The two isomers are easily distinguished after completion of the process claimed, since only the alkylation product in which the 2-carboxyl group is fl-orientated (and consequently the allyl or methallyl group in the rat-orientation) is capable of forming a lactone with the 4fl-hydroxyl group.

' The following examples illustrate the invention:

Example 1 tion is then added dropwise to an ice cold mixture of 11 parts by volume of 4-molar sodium dihydrogen phosphate solution and 19.5 parts by volume of water, the reaction vessel is rinsed with a mixture of 10 parts by volume of phthalein paper is no longer positive, and the mixture is extracted with methylene chloride to separate ofi slight quantities of neutral substances. By cautiously acidifying the, remaining sodium carbonate alkaline solution with 5-mola-r phosphoric acid to a pH value of 5, extracting with methylene chloride, washing the extracts with water, drying with sodium sulfate and evaporating, there is obtained the resulting 2oc-methallyl-2/3-carboxy- 4b,8-methyl-7-ethylene-dioxy-1 :2:3 :4 4aaz4b: 5 6 7 8: 10: 10aB-dodecahydrophenanthrene-1:4B-diol which partially lactonizes in the course of being worked up. The crystalline crude product is dissolved in 130 parts by volume of boiling benzene, the solution is boiled for 3 minutes to complete the lactonization, and the benzene is then distilled in vacuo. The residue is recrystallized from other, using methylenechloride as solution promoter. There is thus obtained the pure (2- 4/3)-lactone of Zea-methallyl- 2fi-carboxy-4b/3-methyl-7 -ethylene-dioxy-1 :2: 3 :4 43cc 4b 5 :6:7:8:10:10a13 dodecahydrophenanthrene- 1:4;8-diol melting at 246249 C.

To a suspension of the chromium trioxide-pyridine complex prepared in a dry atmosphere of nitrogen from water and 5 parts by volume of ethanol and the aqueous solution is concentrated in vacuo at room temperature to 12-15 parts by volume. The resulting suspension is extracted with methylene chloride, the extracts washed with water, dried with sodium sulfate, filtered and evaporated. For the purpose of purification, the residue is dissolved in a mixture of hexane and benzene (9:1) and chromatographed over 49 parts of Florida bleaching earth by the fractional elution method. 7 With mixtures of hexane and benzene (9:1) and (1:1) only insignificant quantities of substance are removed. The fractions extracted with benzene, mixtures of benzene and ether (9:1) and (1:1) yield by recrystallization from petroleum ether pure 20cmethallyl-2,8-carbethoxy 4,3-ethoxycarboxy-4bfl-methyl- 7 ethylene-dioxy 1:2:3:4:4aa:4b:5:6:7:8:10:10afi-d0- decahydrophenanthrene-l-ol melting at 92-945 C.

The same compound is obtained if the following procedure is carried out: To a solution prepared in a dry atmosphere of nitrogen of 12.260 parts of Zea-methallyl- 2B carbethoxylfi-ethoxycarboxy-4b/3-methyl-7-ethylene phenanthrene-l-one in 312.5 parts by volume of anhythe reaction vessel is rinsed with 150 parts by volume of ice cold water. The reduction product is extracted with ether, the ethereal extract washed with Z-molar sodium dihydrogen phosphate solution and with water, dried with sodium sulfate and evaporated. By crystallization of the residue from isopropyl ether and pentane there is obtained 20: methallyl '2/3 carbethoxy-4B-ethoxycarboxy 4b18- methyl 7 ethylene-dioxy l:2:3:4:4aa:4b:5:6:7:8:10:

'10ap dodecahydrophenanthrene-l-ol which" can be obmined in two modifications, of whichthe stable form 25.15 parts of chromium trioxide and 750 par-ts by volume of anhydrous pyridine there is added a solution of 9.363 parts of (2+ 4b)-lactone of 2a-methallyl-2B-ca-rboxy-4bB-methyl-7-ethylene-dioxy-1 2: 3 :4 43cc 4b: 5 6 :7 8:10: 10ao-dodecahydrophenanth-rene-1 :4/3-diol in 250 parts by volume of anhydrous pyridine at once and heated to 60-65 C. for 14 hours with stirring. After cooling, the pyridine is carefully distilled off in vacuo until only a small quantity remains, 500 parts of ice are added to the moist residue and, after adding 625 parts by volume of ice water, the whole is vigorously agitated with a mixture of 3750 parts by volume of ether and 1250 parts by volume of methylene chloride. The resulting emulsion is filtered with suction from the solid portions through a filter aid, the upper phase of the filtrate washed with 4-molar sodium dihydrogen phosphate solution and with water, dried with sodium sulfate and evaporated. The crystalline crude dehydrogenation product is dissolved in benzene, the solution filtered through a layer of activated carbon to remove the color, and the filtrate evaporated in vacuo. By recrystallization of the residue from ether using methylene chloride as solution promoter there is obtained (2- 4e)-lactone of Zea-methallyl 25 carboxy 4bfi-methyl-7-ethylene-dioxy-1:2:3:4: 43.0t14b2516171821021021fi dodecahydrophenanthrene 45- ol-l-one melting at 188-190 C.

Example 2 3.2 parts of the mixture of the 2-allyl-2-carbethoxy- 4B ethoxycarboxy 4bp-methyl-7-ethylene-dioxy-l22:3: 4 4210c 4b 5 6 7 8: 10 10aB-dodecahydrophenanthrene 1- one epimeric at the carbon atom 2, are dissolved in parts by volume of absolute alcohol, 2.5 parts of sodium borohydride are admixed, and the whole allowed to stand at about 20 C. for 3 days. The mixture is then rendered slightly acid with dilute acetic acid, the alcohol evaporated under reduced pressure, the residue taken up in a mixture of chloroform and ether (1:3), washed with water, sodium carbonate solution, and water, and dried over sodium sulfate. The solution is evaporated. and yields 3.13 parts of a crude product from which there is obtained by crystallization from a mixture of ether 3:4:4aa:4b:5:6:7:8:10:10afl dodecahydrophenanthrene 1-01 in the form of fine needles of melting point 180- 182 C.

The mother liquor (2.45 parts) is boiled with parts of potassium hydroxide in 150 parts by volume of alcohol for 2 hours and then 50 parts by volume of water are added. The alcohol is then removed in vacuo and the aqueous mixture extracted with a mixture of chloroform and ether. The extracts washed with water and dried over sodium sulfate yield 0.268 part of residue (neutral part), from which by crystallization from a mixture of ether and petroleum ether 0.168 part of the 2a-hydroxymethyl-2,8-allyl-4b,B-methyl-7-ethylene-dioxy-1 2 3 4 43oz 4b:5:6:7:8:10:10a/3 dodecahydrophenanthrene 1:45- diol and melting at 182-184 C. (transformation at 165 C.) is isolated. The alkaline aqueous extracts are mixed with hydrochloric acid until the reaction is acid to Congo and extracted with chloroform. These extracts yield 1.39 parts of residue (acid-t-lactone). By crystallization from a mixture of acetone and ether there is obtained 0.73 part of (2 4fi)-lactone of 2a allyl 2,8 carboxy 4b,6- methyl 7 ethylene dioxy 1:2:3:4:4aa:4b:5:6:7:8: :10afi-dodecahydrophenanth-rene-l:4B-diol melting at 233-237 C. The mother liquor is dissolved in a mixture of chloroform ether (3:1) and by extraction with a solution of sodium carbonate separated into acid and neutral portions. There is obtained 0.43 part of neutral product and 0.22 part of acid product. From the neutral portion there is obtained a further 0.225 part of the above lactone. The acid portions yield from ether the 204 carboxy-Zfi-allyl-4b;B-methyl-7-ethylene-dioxy-l 2 2:3 4:4aaz4b 5 2 6 7 8: 10: IOa/i dodecahydrophenanthrenel34j3-Cli0l melting at 216-222 C.

1.2 parts of chromium trioxide are added in portions to 12 parts by volume of pyridine and mixed with 0.55 part of the above described lactone melting at 233237 C. in 6 parts by volume of pyridine. The mixture is heated under nitrogen for 6 hours at 6065" C., then diluted with chloroform, filtered and the residue washed with chloroform. The filtrate is evaporated in vacuo almost to dryness, the residue is taken up in a mixture of chloroform and ether and washed with Water, hydrochloric acid, sodium carbonate solution and water. The solution dried over sodium sulfate is evaporated and the residue crystallized from a mixture of acetone and ether. There is obtained 0.36 part of the (2 4p)- lactone of 2a-allyl-ZB-carboxy-4bB-methyl-7-ethylene-dioxy -1:2:3:4:4aa:4b:5:6:7:8:10:10afi dodecahydrophenanthrene-1-one-4B-ol melting at 185-189 C.

Example 3 The starting material used in Example 1 is prepared as follows:

4.4 parts of 4b;8-methyl-2-carbethoxy-4B-ethoxy-carboxy 7 ethylene-dioxy-l:3:4:4aa:4b:5:6:7:8:10:10a18- dodecahydrophenanthrene-l-one in 20 parts by volume of absolute dioxane are reacted in a stirring vessel charged with glass balls in an atmosphere of nitrogen with 0.5 part of sodium hydride at room temperature, 3 parts by volume of methallyl iodide are introduced dropwise, and the whole is stirred for 6 hours at 55-65 C. After cooling the reaction'mixture there are added first 5 parts by volume of ethanol, then, after diluting the mixture with a large amount of benzene, 20 parts of ice, and then the whole is stirred for a few minutes while cooling. The aqueous phase is separated from the organic phase and the latter is agitated with ice water. After drying and removing the solvent in vacuo there is obtained 4bB methyl-2-methallyl-2-carbethoXy-4,8-ethoxy-carboxy- 7 ethylene dioxy 1:2:3:4:4aa:4b:5:6:7:8:102102113- dodecahydrophenanthrene-l-one as a reddish oil. The

. droxide and ice water.

separation into the two compounds isomeric at the carbon atom 2 is described below.

The 4b,8-methyl-2-carbethoxy-4fl-ethoxy-carboxy-7-ethylene dioxy-1:2:3:4:4aa:4b:5:6:7:8:10:IOafi-dodecahydrophenanthrene-l-one is prepared as follows:

4 parts of 4bfi-methyl-7-ethylenedioxy-1:2:3:4:4aa:4b: 5 6 7 8: 10: 10afl-dodecahydrophenanthrene-4B-ol-1 one in 12 parts by volume of diethyl carbonate and 20 parts by volume of absolute dioxane are stirred in a stirring vessel charged with glass balls in an atmosphere of nitrogen with 2 parts of sodium hydride for 12 hours at 55-65" C. After cooling, the reaction mixture is mixed with 10 parts by volume of ethanol, then diluted with benzene and extracted by agitation twice with a small quantity of ice water. The benzene solution is dried with potassium carbonate and, after removing the solvent in vacuo, yields 4ba-methyI-Z-carbethoxy-4,8-ethoxy-carboxy 7 ethylene dioxy -1;2:3:4:4aot:4b:5:6:7:8:l0: 10a,8-dodecahydrophenanthrene-l-one, which is obtained by crystallization from petroleum ether in the form of colorless crystals melting at 115 C.

A mixture of 10.673 parts of 2-carbethoxy-4B-ethoxycarboxy 413/3 methyl-7-ethylene-dioxy-1 22:3 :4I4Etoc24b1 5 6:7 8: 10: 10afi-dodecahydrophenanthrene-l-one, 8.342 parts of finely pulverized anhydrous potassium carbonate, 183 parts by volume of anhydrous acetone and 69.4 parts by volume of methallyl iodide is vigorously stirred for 40 hours in an atmosphere of nitrogen at room temperature. It is then evaporated in vacuo at a temperature of at most 25 C., the residue is taken up in ice water and a mixture of ether and benzene (2:1), the organic phase is extracted at 0 C. with 1 N-potassium hydroxide and water, dried with sodium sulfate and evaporated in vacuo. By recrystallization from a mixture of isopropylether and petroleum ether there is obtained the pure 2a-methal1yl-ZB-carbethoxy-4,8-ethoxy-carboxy- 4b}? methyl 7-ethylene-dioxy-l :2:3:4:4au:4b:5:6:7:8: l0:10aB-dodecahydrophenanthrene-1-one melting at 99.5- 101" C.

The residue obtained by evaporating the mother liquor is dissolved in a mixture of hexane and benzene (9:1) and chromatographed over 240 parts of aluminum oxide. As elutriating agents there are used successively mixtures of hexane and benzene (9:1) and (1:1) and benzene.

From the first elutriate of hexane and benzene 1:1) there is obtained by crystallization from a mixture of isopropyl ether and petroleum ether a further quantity of pure 2a-methallyl-ZB-carbethoxy-4B-ethoxycarboxy- 4b;3 methyl 7-ethylene-dioxy-1:2:3:4:4aot:4b:5:6:7:8: 10: l0afl-dodecahydrophenanthrene-1-one melting at 99.5- 101 C. The subsequent fractions obtained with hexane and benzene (1:1) and benzene yield when crystallized from ethanol of percent strength pure epimeric 2B methallyl-2a-carbethoxy 4 8-ethoxycarboxy-4bfi-methyl 7 ethylene-dioxy-l:2:3:4:4aot:4b:5:6:7:8:10:10afldodecahydrophenanthrene-l-one melting at 94.595.5 C.

The 2-carbethoxy-46-ethoxycarboxy-4bflmethyl-7-ethylene dioxy-1:2:3:4:4aa:4b:5:6:7:8:10:l0a/8-dodecahy drophenanthrene-l-one used as starting material can be prepared as follows:

To a suspension of 5.848 parts of 4bB-methyl-7- ethylene dioxy-1:2:3:4:4au:4b:5:6:7:8:10:10aB-dodecahydrophenamthrene-1-one-4B-ol in 48.50 parts by volume of diethyl carbonate there are added 1.77 parts of sodium hydride and the mixture is stirred in an atmosphere of nitrogen first for 4 hours at room temperature and then 12 hours at 55 60 C. bath temperature. The reaction mixture is then cautiously mixed with 40 parts by volume of an anhydrous mixture of ethanol and ether (1:10) at 0 C. to destroy the excess sodium hydride and, after diluting with 98 parts by volume of ether, it is extracted successively with ice water, ice cold 1 N-potassium hy- The ethereal solutions are dried with sodium sulfate and evaporated, the diethyl carbonate is removed in high vacuum, and the residue crystallized from a little ether. In this way there is obtained the pure 2-carbethoxy-419-ethoxycarboxy-4bfl-methyl-7-ethylene-dioxy-l :2:3 :4:4aa:4b:5 6:7 :8: l: IOaB-dodecahydrophenanthrene-l-one melting at 1l5-l16 C.

. Example 4 The starting material used in Example 2 is prepared as follows:

To a suspension of 1.311 parts of 2-carbethoxy-4fl-ethwhole is stirred for 48 hours under nitrogen at 25-28 C.

The mixture isthen concentrated in vacuo at 30 C. bath temperature to about parts by volume, diluted with a mixture of benzene and ether (1:1) and washed with ice-water, ice-cold 1 N-caustic soda solution and water.

The benzene-ether-solution dried with magnesium sulfate yields on evaporation 1.548 parts of a yellow oil. For the purpose of purification this crude product is chromatographed on 50 parts of aluminum oxide (activity 11). With a mixture of hexane and benzene 9:1 only traces of impurities are removed, whilst with a mixture of hexane and benzene 1:1 a total of 1.265 parts of the two 2-allyl-2- carbethoxy-4fi-ethoxy-carboxy-4bB-methyl-7-ethylene dioxy-l:2:3:4:4aa:4b:5:6:7:8: 10: 1021p dodecahydrophenantherene-l-ones epimeric at the carbon atom number 2 are extracted as a colorless oil which show no coloration To a solution of 5 parts of 2-carbethoxy-4/3-ethoxycarboxy-4bfi-methyl-7-ethylene-dioxy 1 :2:3 :4:4aa-4b:5 6:728: 10: 10afl-dodecahydrophenanthrene 1 one in parts by volume of acetone (anhydrous) there are added 4.5 parts of freshly calcined potassium carbonate, 35 parts by volume of allyl chloride and 3 parts of dried potassium iodide. The mixture is agitated for 3 days under nitrogen. It is then concentrated in vacuo at 30 C. to about 10 parts by volume, taken up in a mixture of chloroform and ether, washed with ice water, twice with ice-cold l N-caustic soda solution, then with water, and dried over sodium sulfate. The evaporated solution yields 5.38 parts of crude product which are chromatographed onparts of aluminum oxide.

The fractions extracted with mixturesof benzene and petroleum ether, pure benzene and benzene with 5% ether weigh 3.4 parts, are amorphous and consist of a mixture 'of the two 2-allyl-2-carbethoxy-4B-ethoxycarboxy-7-ethylene-dioxy-l:2:3:4:4aa:4b:5:6:7:8:10:10ap-dodecahydro phenanthrene-l-onesepimeric at the carbon atom number The fractions extracted with mixtures of ether and benzene, ether alone, chloroform and chloroform with 5% methanol yield from ether-petroleum ether 1.060

lower alkyl and R for a member selected from the group consisting of 'a hydrogen atom and a methyl group with an alkalimetal borohydride, hydrolysing the ester functions in the hydroxyl compound obtained under alkaline conditions, acidifying the reaction mixture and dehydrogenating the free hydroxyl group in the 1-position of the (2- 4)-lactones obtained to an oxo group.

2. Process according to claim 1, wherein sodium borohydride is used as reducing agent.

3. Process according to claim 1, wherein the pyridinechromium trioxide complex is used as an oxidizing agent.

4. Process according to claim 1, wherein the Zea-methallyl-213-carbethoxy-413-ethoxycarboxy-4bB-methyl-7-ethylenedioxyl:2:3:4:4aa:4b:5:6:7:8:10:10a18 dodecahydrophenanthrene-l-one is used as starting material.

5. Process according to claim 1, wherein the Zea-allyl- ZB-carbethoxy-4 3-ethoxycarboxy-4bp-methyl-7-ethylenedioxy -1:2:3:4:4aa:5:6:7:8:10:10ap dodecahydrophenanthrene-l-one is used as starting material.

6. A compound of the formula R0000 COOR wherein R stands for lower alkyl and X represents lower alkylenedioxy.

7. The compound of the formula ogmoooo 0000,11,

8. A compound of the formula R0000 on,

wherein R stands for lower alkyl, R' for a member selected from the group consisting of a hydrogen atom and ,a methyl group, -X' represents a member selected from oimocoo H.

' 1 1 12 wherein R stands for a member selected from the group 15. The compound of the formula consisting of a hydrogentatom and methyl group and .X' o for a member selected from the group consisting of O and H(OH).

10. The compound of the formula V 5 l CZHBOO 0 0 CH: 0

16. A compound of the formula V R O 7 O-C O 11. The compound of the formula CH: l 000023, (hem x 021150000 0H1 wherein R represents a member of the group consisting of hydrogen and methyl, X is a member of the group 011 consisting of O and H(OH) and X represents lower alkylenedioxy. 17. A compound of the formula:

RO()O CH:C=CH2 12. A compound of the formula H a R J 0-00 (them (|3H10 CH2 7 CH2 O/ I V in which X" is selected from the group consisting of O and x H(OH), and R is lower alkyl.

49 18. A compound of the formula:

X fo o=0 CH3 -CH2C=CH| wherein R stands for a member of the group consisting of a hydrogen atom and a methyl group, X for a member i I p of the group consisting of O and H(OH) and X represents lower alkylenedioxy. CHa-O 13. A compound of the formula CHPO/ 50 in which X is selected'from the group consisting of O and H O 1 H(OH).

6 19. Acompound of the formula: CH:

t 7 CH: 000cm, {1 Q oirnoooo I: 7 OH O a so 0 wherein X stands for a member of the group consisting of I: O and H(OH). 0 14. The compound of the formula 20. A compound of the formula:

I 0003 C=CH5 l on O 21. A compound of the formula:

22. A compound of the formula:

I OH

14 23. A compound of the fromula:

GH=CH1 References Cited in the file of this patent Schmidlin et al.: Experientia, vol. XI, pp. 365-368, 15 September 15, 1955. 

8. A COMPOUND OF THE FORMULA
 15. THE COMPOUND OF THE FORMULA 